P RIMER ARTÍCULO

Referencia: Sanz J, Zhao M, Rodríguez N, Granado R, Foro P, Reig A, et al. Once-Weekly Hypofractionated Radiotherapy for Breast Cancer in Elderly Patients: Efficacy and Tolerance in 486 Patients. Biomed Res Int. 2018;

148

149

Clinical Study

Once-Weekly Hypofractionated Radiotherapy for Breast Cancer in Elderly Patients: Efficacy and Tolerance in 486 Patients

Javier Sanz ,^1,2Min Zhao,³Nuria Rodríguez,^1,2Raquel Granado ,¹Palmira Foro ,^1,2 Ana Reig ,¹Ismael Membrive ,¹and Manuel Algara ^1,2

1Radiation Oncology Department, Hospital del Mar, Parc de Salut Mar, Barcelona, Spain

2Pompeu Fabra University, Barcelona, Spain

3Autonomous University of Barcelona, Barcelona, Spain

Correspondence should be addressed to Javier Sanz; jsanz@parcdesalutmar.cat

Academic Editor: Pierfrancesco Franco

Copyright ©2018Javier Sanz et al.This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Purpose. Radiation therapy is a key treatment of breast cancer. Elderly patients with associated diseases that modify their performance status do not tolerate long periods of daily irradiation.The objective of this study is to analyze the results of weekly hypofractionated treatment in these patients.Material and Methods. Between1992and2016, we included486elderly patients presenting concomitant pathology or sociofamilial problems in which it was not feasible to propose conventional treatment.They were treated with conservative surgery or mastectomy and then adjuvant hypofractionated irradiation, administering5Gy or 6.25Gy in6fractions, once a week (total dose30–37.5Gy) over6weeks.Results. Breast cancer overall survival according to the Kaplan-Meier method at5years was74.2%± 2.3%; breast cancer disease-free survival was90%± 1.6%; local relapse-free survival was96.5%± 1% showing that patients die more from other causes and not from their neoplasia. Acute dermatitis was mild (75.6%

of the patients grades I–III) and30.6% had moderate chronicfibrosis.Conclusions.The once-weekly hypofractionated radiotherapy is a feasible and convenient option for elderly patients with breast cancer. It is a safe treatment modality with similar survival and local control results compared to standard fractionation, while the side effects are acceptable.

1. Introduction

Breast cancer is the most common tumor in women [1].

The incidence rate continues to increase slowly in both developed and underdeveloped countries. It is the leading cause of cancer mortality in women. Survival of breast cancer has really improved in the last20years, approximately 1.4% annually [2], mainly due to the early detection of this neoplasm, improvements in surgical techniques, systemic treatments, and radiotherapy.

The treatment of breast neoplasia combines surgery, systemic treatment, and radiotherapy. The most common regimen for the complementary treatment of breast cancer after conservative [3] or radical surgery has been the standard fractionation, consisting of 45–50Gy in25fractions of1.8 or2Gy/day,5days a week, for33days [4,5].These studies show that the incidence of local recurrence is significantly

lower in the group of patients treated with radiotherapy, about an8%–10% with respect to the nonirradiated ones in which the local recurrence reached25%–35%, independently of other associated factors. One of the most important risk factors for the development of breast cancer is age [6].

Most cases are diagnosed between the ages of35 and80, nearly half of them diagnosed at the age of 70 or more years [7]. Currently, approximately 30% of patients in a radiotherapy department have breast cancer [8]. Elderly patients are frequently associated with concomitant diseases, cognitive impairment, sociofamilial problems, or functional limitation [9]. Patients often live far from the hospital and have difficulty to attend the radiotherapy sessions.Therefore, according to established practice, it is not always feasible for elderly patients to indicate a conventional, daily treatment [10].This may lead to individuals avoiding complementary treatment after conservative surgery, or unnecessary abuse of

Hinda i

BioMed Re ea ch In e na ional Vol me 2018, A icle ID 8321871, 9 age h ://doi.o g/10.1155/2018/8321871

150

2 BioMed Research International

radical mastectomy in the initial stages, which results in an undertreatment or overtreatment in a large number of cases.

Therefore, it is advisable to plan a more convenient treatment regimen for the elderly patients while a similar local control result can be achieved.

Today, although the current standard is moderate daily hypofractionation, there are still many patients who cannot tolerate it and require a more adapted treatment to their condition.There are other fractionation schedules that can shorten the radiation treatment, demonstrating the same efficacy, without increasing complications. Aside improve-ment in quality of life [11], also short treatimprove-ments can relieve the pressure of medical resources and logistical problems of access to the radiotherapy. One of the current challenges is the definition of irradiation schedules that are more comfortable for patients and easier to integrate with systemic therapies. In any case, there is no clear consensus on what should be used on a regular basis [12,13].

The purpose of the present observational study is to analyze the results of weekly hypofractionated irradiation treatment in older patients with breast cancer in terms of survival, locoregional control, tolerance, and acute and chronic toxicity.

2. Materials and Methods

2.1. Patient Selection. Elderly patients with nonmetastatic breast neoplasia treated between1992and2016 have been included. Inclusion criteria have been patients older than 70 years and/or those patients who do not tolerate daily travel to our radiotherapy department for several reasons such as those associated with concomitant diseases, cognitive impairment (according to the global deterioration scale or GDS of 4 or higher), sociofamilial problems, functional limitation, or living away from the treatment center. The criteria for the choice of initial surgery were the same as those used for young patients. So patients with I-II stages underwent conservative treatment and lymphadenectomy (or sentinel node selective biopsy), and patients with stage III were submitted to radical treatment with mastectomy and lymphadenectomy. In patients with conservative surgery, the margins were considered positive if the tumor reached the ink of the sample or close when they were negative but inferior to 3mm.The characteristics of the patients are shown in Table1.

2.2. Treatment. They received weekly hypofractionated irra-diation within 2 months after surgery. The patients were treated with a cobalt unit or a linear accelerator by means 3D conformal tangential beams to the breast volume or field infield modulated techniques to optimize dosimetric distribution. All patients were treated in supine position, with abduction of ipsilateral arm utilizing an alpha-cradle immobilization.

The radiation schedule consisted of6.25Gy per fraction once a week but in the recent part of the series the fraction was reduced to5Gy with the aim of reducing the risk of secondary effects. Patients treated with conservative surgery or only biopsy received irradiation to the breast and mastectomized patients to the chest wall. In patients with T4tumors treated

Table 1: Characteristics of the patients.

n %

with electrons to the chest wall a bolus was utilized. Patients with positive surgical margin were considered to receive radiotherapy to the tumor bed by adding1or2additional weekly doses at this level.The boost volume consisted in the tumor bed marked with clips and additional margin of15mm in all directions to obtain the PTV.The supraclavicular fossa was irradiated as a function of the nodal involvement, always in N2cases and in patients with N1involvement treated in the period from 2008 to 2016 according to our guideline and evidence published data [14]. In these cases, additional anterior and posterior fields to supraclavicular fossa and lymph node level III were utilized.

2.3. Evaluation and Follow-Up. All patients were evaluated weekly after the session for tolerance and underwent control of acute and chronic local toxicity according to the RTOG scale or the Common Terminology Criteria for Adverse Events v4.0(CTCAE), indicating supportive treatment when necessary. Patients were followed periodically after the end of treatment, at a month,6months, and subsequently at least once a year.

Patients were included following the ethical principles for medical research according to Helsinki declaration and an informed consent was obtained from all the patients.

2.4. Statistical Analysis. The statistical analysis was per-formed with SPSS v22(IBM SPSS, Chicago, IL). Chi-square and exact Fisher tests were employed to evaluate categorical variables. The actuarial rates of overall survival, disease-free survival, local relapse-disease-free survival, and metastasis-free survival were calculated according to the Kaplan-Meier method and comparisons were made using the log-rank test.

3. Results

3.1. Patients and Treatment Characteristics. Four hundred and eighty-six patients have been included. The median

151

BioMed Research International 3

age of patients was 79 ± 6.5 years (range 58–97). Half of the patients lived outside Barcelona, which makes it more difficult for them to get to the hospital. Breast conservative surgery was performed in 78.6% (73.3% tumorectomy and 5.3% quadrantectomy) and total mastectomy in20% and only biopsy in0.6% were performed by associated pathology that contraindicated the intervention or occasionally because of the refusal of the patient to be operated on. Patients without chemotherapy were treated postoperatively at 2.2 months (range:1–3months), and patients with adjuvant chemother-apy were treated 4.5 months (range:2.5–4.6months) after surgery. Hormonal therapy was utilized in78.7% of the cases;

among them57.8% were treated with aromatase inhibitors. In 13.4% of the patients neoadjuvant or adjuvant chemotherapy was administered, mainly anthracyclines, taxanes, or CMF schedules.

Patients were treated in 13.4% of cases using 1.25MV photons of a Cobalt-60 unit or by means of a linear accelerator unit so that 69.3% of the cases were treated with 6MV photons (337 patients), and 17.3% of the cases corresponding to mastectomized patients were treated with electrons (84 patients). 80.7% of cases received a total of 6 sessions. 90.7% of patients received a fractionation of 6.25Gy/fraction and9.3% (45patients) at5Gy/fraction up to a total dose of30Gy. An amount of17.5% of patients with positive surgical margin after conservative surgery received a boost to the tumor bed of 1 or2 additional doses (7.2%

and 10.3% of patients, resp.). None of the patients treated with mastectomy received a boost. In15% of the series, the patients received irradiation to the supraclavicular fosa and axillar level III cause of positivity of lymph nodes in the lymphadenectomy. Only9patients (1.8%) did not complete the treatment (1 patient received 4sessions and8 patients received 5 sessions) mainly due to complications of their comorbidities.

3.2. Recurrence and Survival. Local control was excellent, reaching96.5%±1% at5years, and only16patients had local recurrence. After a median follow-up of51months (range:

1–163months), the status of the patients was as follows:341 (70%) were disease-free,45(9.3%) died as a result of cancer progression, and95(19.5%) died of another disease. Mortality was more frequently caused by concomitant diseases than by neoplasia.

So, overall survival according to the Kaplan-Meier method at 5years was74.2%±2.3%; breast cancer specific survival was90%±1.6%; relapse-free survival was96.5%± 1%; metastasis-free survival was 90% ± 1.6% (Figure 1).

Estimated survival at5years according to the disease stage is presented in Figure 2: Patients with grade 1-2 histology had better survival rates than those of grade3(𝑝 = 0.002).

Survival according to the histologic grade at5years is shown in Figure2.

Survival according to the positivity of estrogen receptors was also significant. So, patients who had positive estrogen receptors have better survival than those whose receptors were negative. Overall, survival according to progesterone receptor is not statistically significant.

3.3. Treatment Tolerance and Toxicities. The acute toxicity is presented in Figure2. Among patients who have presented dermatitis, half of them were grade1. Usually, the cases of acute dermatitis were resolved in1-2months with the appro-priate topical moisturizing treatment for patients who have presented dermatitis grades1and2and with sulphadiazin cream for patients with grade3.There were no differences in skin toxicity according to the treatment unit or the techniques utilized for irradiation (𝑝 = 0.092 and 𝑝 = 0.174 for acute and chronic toxicity, resp.). When comparing acute toxicity among the fraction utilized, patients with5Gy per session presented dermatitis grade1in65%, grade2in30%, and grade 3 in 5%, and the patients treated with6.25Gy presented dermatitis grades1, 2, or 3in 47%, 32.6%, and 13.7%, respectively. In terms of chronic toxicity, 30.9% of the patients presented skin impairment (Figure3). Among them,88% presentedfibrosis,8.7% had hyperpigmentation or telangiectasia, and3.3% had edema or mastitis. Among patients withfibrosis, only one patient was grade IV. The reporting of symptoms related to breast fibrosis was very unusual. Chronic toxicity was lower in patient treated with 5Gy per session compared to patients treated with6.25Gy per session schedule (22.9% and31.4%, resp.;𝑝= 0.34).There were no cases of pulmonary or thoracic sequelae in terms of pneumonitis or rib fracture.

4. Discussion

Complementary radiotherapy is classically indicated for patients who have undergone conservative surgery for all types of infiltrating tumors and many intraductal carcinoma tumors.The volume to be treated includes the entire breast with a total dose between45and 50Gy, at a daily dose of 1.8–2Gy as a classical or standard fractionation.The good results obtained with the conservative treatment provoke a new attempt to reduce the therapeutic aggressiveness, in this case focused on the radiotherapy. Hypofractionation programs are being developed in order to reduce the number of sessions, so as to increase patients’ comfort, especially the comfort of elderly patients.

There is abundant experience in the hypofractionated treatment in patients with breast cancer (Table2). Shelley et al. [15] demonstrated in a phase II study with294patients that treatment based on40Gy in16fractions of2.5Gy and in22 days after a mean follow-up of5.5years achieved a relapse-free survival of96.5% which had no difference in acute or chronic local toxicity. In2010, Whelan demonstrated in his study with more than1200 patients receiving50Gy in 25 fractions or42.56Gy in16fractions, after a10-year follow-up, that there were no significant differences in local recurrence (6.7% versus6.2%) and good aesthetic results were achieved (71.3% versus69.8%, resp.). Acute toxicity of grade3or higher was only present in3% in each group [11]. In the START-A trial, a regimen of50Gy in25fractions over5weeks was compared with41.6Gy or39Gy in13fractions over5weeks [16]. In START-B trial, a regimen of 50Gy in25fractions over5weeks was compared with40Gy in15fractions over 3weeks [17]. After approximately 10 years of follow-up, it has been confirmed that moderately daily hypofractionated

152

4 BioMed Research International

Overall survival by disease stage

Stage I

0.00 p value log-rank test = 0.0073

0 30 60 90 120

0.00 p value log-rank test = 0.000

0 30 60 90 120 Overall survival by differentiation grade

1.00 0.75 0.50 0.25

0.00 p value log-rank test = 0.0141

0 30 60 90 120

Disease-free survival by differentiation grade 1.00

0.75 0.50 0.25

0.00 p value log-rank test = 0.023

0 30 60 90 120

Figure 1: Overall and disease-free survival curves according to stage (a and b) and according to histologic grade (c and d).

irradiation is safe and effective for patients with early breast cancer.These results support the use of40Gy in15fractions (3weeks), which has already been adopted by most centers as the standard therapy for women who require adjuvant radiotherapy for early stage invasive breast cancer.

More recently, results of the UK IMPORT LOW trial have been published. In this trial the patients were randomized to receive whole breast irradiation at a dose of40Gy in15 fractions,36Gy to whole breast and40Gy to the partial breast (reduced-dose group) or40Gy to the partial breast only.This trail has showed noninferiority of partial breast and reduced-dose radiotherapy compared with the standard whole breast hypofractionated irradiation [18]. Also the same research group is investigating, in the HIGH IMPORT Trial, the

intensification of hypofractionated treatments by comparing the whole breast irradiation of40Gy plus a sequential boost of16Gy (control group) with two test arms: arm1consisting in whole breast irradiation up to36Gy, the index quadrant up to 40Gy, and concomitant boost up to 48Gy in 15 fractions, or arm 2with whole breast receiving 36Gy, the index quadrant receiving40Gy, and a concomitant boost up to53Gy, also in15fractions.The trial is under recruitment.

From the radiobiological point of view, the limits to avoid increase in chronic toxicity seem to be about3.2–3.3Gy per fraction as reported by Qi et al. [19].

Although the 3-week daily schedule is a significant improvement compared to the traditional5-6-week schedule, the requirements of daily therapy continue to be problem in

153

Figure 2: Acute toxicity and dermatitis grade according to RTOG criteria.

0

Figure 3: Chronic toxicity (any type) andfibrosis grade rates according to CTCAE v4.0criteria.

regions with limited oncology care resources and in some cases the patients are excluded to receive appropriate postop-erative treatment [20]. Favorable results from the randomized trials of the hypofractionated schedules described above have provided enough data to allow further investigation towards still more concentrated hypofractionated schedules with fewer sessions.

Thefirst published clinical trial of once-weekly hypofrac-tionated radiotherapy regimen was carried out in1987and published by Rostom et al. [21]. It was a phase II trial that

applied a dose per session of6.5Gy/day, one session per week to older patients. It demonstrated a good locoregional control result and an acceptable cosmetic outcome. In2006, Ortholan et al. published a similar study that included 150patients undergoing both conservative and radical surgical treatment, using the same weekly hypofractionation schedule, in which a good clinical outcome was also demonstrated [22]. Other similar published studies have also shown similar locore-gional control rates, with a slightly higher but acceptable chronic toxicity in most series [23–25]. More recently Dragun

154

6 BioMed Research International

Table 2: Moderate daily hypofractionation and weekly hypofractionation schedules in breast cancer.

(a) Daily hypofractionated schedules

Author n RDT schedule Commentary

Shelley et al.,2000[15] 294 40Gy in2.5Gy/s,22days

Deutsch,2002[38] 47 Different schedules since

50Gy in2Gy to36Gy in3Gy 80–89years old Whelan et al.,2002[39] 1234 Standard schedule50Gy in2Gy/s,35days,

versus

hypofraction42.5Gy in2.65Gy/s,22days

Yarnold et al.,2005[37] 1410 50Gy in2Gy/s,39Gy in3Gy/s,

42.9Gy inor3.3Gy/s

Haviland et al.,2013[28] 2236

START A:50Gy in2Gy/s versus41.6Gy or 39Gy in13s

START B:50Gy in2Gy/s versus40Gy in 15s

(b) Weekly hypofractionated schedules

Author n RDT schedule Commentary

Rostom et al.,1987[21] 84 6.5Gy×6s

Courdi et al.,2006[24] 115 6.5×5s Median age83years, biopsy

only RDT: radiation therapy; s: session; p: patient.

et al. have published a phase 2 study which included 42 patients who underwent conservative surgery and received weekly hypofractionated irradiation at6Gy/week in5weeks, total dose at30Gy, demonstrating the feasibility of the weekly schedule. At the same time, it was cost effective and had low acute toxicity rates, although further monitoring is required to confirm long-term results with a possible reduction of chronic toxicity according to dose reduction per fraction [26].

These results have been also confirmed in another series of Rovea et al. where 291 patients received 30 or32.5Gy in 5fractions, with mild chronic toxicity in terms offibrosis,

edema, or hyperpigmentation and also achieving good or excellent cosmetic result in86.4% of cases [27].

A common criticism of these studies regards their lim-ited applicability in that they include mainly lymph-node-negative, postmenopausal patients with biologically favorable early stage invasive disease [28]. In the present study, we included486patients, the majority in early stage, who have received5Gy or 6.25Gy in6 sessions with 1-2additional fractions if they have the positive surgical margin. Treatment tolerance was assessed and considered satisfactory. Long-term toxicity was greater. Such toxicity was acceptable taking

155

BioMed Research International 7

into consideration the fact that it rarely seems to impact patients’ quality of life, as most cases have been reported as asymptomatic along the follow-up.The results regarding specific survival and local control were similar to the standard treatment and matched with the series already published, stressing that the survival of these older patients is more influenced by their own comorbidities than for the evolution of breast cancer, leading to a specific survival of90% at5years.

into consideration the fact that it rarely seems to impact patients’ quality of life, as most cases have been reported as asymptomatic along the follow-up.The results regarding specific survival and local control were similar to the standard treatment and matched with the series already published, stressing that the survival of these older patients is more influenced by their own comorbidities than for the evolution of breast cancer, leading to a specific survival of90% at5years.